Journal of Molecular Biology
Volume 428, Issue 20, 9 October 2016, Pages 4115-4128
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Contribution of Bistability and Noise to Cell Fate Transitions Determined by Feedback Opening

https://doi.org/10.1016/j.jmb.2016.07.024Get rights and content
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Highlights

  • The rates of transition between two cell fates or states are difficult to predict because of missing parameters and the strong effect of noise.

  • We predict the rates with a method termed feedback opening; the predictions are in good agreement with the observed rates.

  • When feedback loops are opened experimentally, the resulting open-loop function determines whether the parent feedback loop has one or two stable states.

  • Hysteresis may be absent in bistable feedback loops.

Abstract

Alternative cell fates represent a form of non-genetic diversity, which can promote adaptation and functional specialization. It is difficult to predict the rate of the transition between two cell fates due to the strong effect of noise on feedback loops and missing parameters. We opened synthetic positive feedback loops experimentally to obtain open-loop functions. These functions allowed us to identify a deterministic model of bistability by bypassing noise and the requirement to resolve individual processes in the loop. Combining the open-loop function with kinetic measurements and reintroducing the measured noise, we were able to predict the transition rates for the feedback systems without parameter tuning. Noise in gene expression was the key determinant of the transition rates inside the bistable range. Transitions between two cell fates were also observed outside of the bistable range, evidenced by bimodality and hysteresis. In this case, a slow transient process was the rate-limiting step in the transitions. Thus, feedback opening is an effective approach to identify the determinants of cell fate transitions and to predict their rates.

Abbreviations

TF
transcription factor
dox
doxycycline
ORF
open reading frame
smFISH
single molecule fluorescence in situ hybridization
S
logarithmic sensitivity
fOLM
open-loop function
fEQ
equivalence function
Smax(ω)
maximal sensitivity of the fOLM
rtTA
reverse tetracycline transactivator
GEV
Gal4-estrogen receptor-Vp16
GFP
green fluorescent protein
I.C.
initial condition

Keywords

positive feedback loop
stochastic gene expression
synthetic biology

Cited by (0)

C.H. and V.J. contributed equally to this work.